Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1β-mediated increase in E-selectin expression

Abstract

The tumor premetastatic niche initiated by primary tumors is constructed by multiple molecular factors and cellular components and provides permissive condition that allows circulating tumor cells to successfully metastasize. Myeloid-derived suppressor cells (MDSCs), a population of immature cells in pathological conditions, play a critical role in the formation of the premetastatic niche. However, few researches are focused on the function of monocytic MDSCs (mo-MDSCs), a subtype of MDSCs, in the construction of the niche. Here, we show that the number of mo-MDSCs is significantly increased in the premetastatic lungs of tumor-bearing mice, thus promoting tumor cell arrest and metastasis. Before the arrival of tumor cells, the lung-recruited mo-MDSCs produced IL-1β, thereby increasing E-selectin expression and promoting tumor cell arrest on endothelial cells. Depletion of mo-MDSCs in the premetastatic lungs decreased IL-1β production, resulting in reduced E-selectin expression. In addition, compared with alveolar macrophages and interstitial macrophages, mo-MDSCs were the major source of IL-1β expression in the premetastatic lungs. Cytokine array analyses and transwell experiments revealed that CCL12 recruits mo-MDSCs to premetastatic lungs. CCL12 knockdown in tumor-bearing mice significantly decreased mo-MDSC infiltration into the premetastatic lungs, leading to reduced E-selectin expression. Overall, the permissive conditions produced by the infiltrated mo-MDSCs correlated with increased tumor cell arrest and metastasis. These results reveal a novel role of mo-MDSCs in constructing the premetastatic niche. Thus, inhibition of mo-MDSCs infiltration may change the premetastatic niche to normal condition and attenuate tumor metastasis.

Interleukin-1 Beta—A Friend or Foe in Malignancies?

“…Furthermore, the number of monocytic (mo-)MDSC was significantly increased in the prematastatic lungs of tumor-bearing mice, thus promoting tumor cell arrest on endothelial cells and metastasis [245]. The translational importance of IL-1β as a driver of MDSC propagation is underlined by the finding that in peripheral blood of advanced melanoma patients an increased level of serum IL-1β was associated with the frequency of mo-MDSC and Treg.…”

“…It was also revealed, that IL-1β expression in lungs of melanoma-bearing mice is facilitated by lung-recruited mo-MDSC, resulting in enhanced E-selectin expression [245]. …”

“…It could be shown that the number of mo-MDSC is significantly increased in the lungs of melanoma-burdened mice before the arrival of tumor cells. These MDSC secreted IL-1β, resulting in the expression of E-selectin in endothelia cells, being attributed to increased distant metastasis in the lung [245]. Primary tumor cells enable a distant engraftment by secretion of different growth factors [265], resulting in chemokine and cytokine upregulation in the metastatic targeted organ.…”

“…Upregulated expression of proinflammatory chemokines and cytokines resulted in recruitment of bone marrow-derived hematopoietic cells [267]. Mo-MDSC are a significant component of these recruited cells [245]. …”

The Interaction of Selectins and PSGL-1 as a Key Component in Thrombus Formation and Cancer Progression

“…Consequently, an E-selectin targeted aptamer could reduce hematogenous metastases of breast cancer in a mouse model [85]. Very recently, myeloid-derived suppressor cells have been shown to promote the arrest of cancer cells via IL-1 β -mediated E-selectin expression on endothelial cells [86]. In turn, activated endothelium produces several chemokines (CCL5) to support the extravasation of cancer cells [71, 79, 87].…”